Evidence for resistance to MPTP in C57BL/6 × BALA/c F1 hybrids as compared with their progenitor strains

Abstract

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is capable of producing a syndrome in mice which shares major characteristics with human Parkinson's disease. There is evidence for a genetic influence on the degree of damage exerted by MPTP, since different strains of mice can dramatically differ in their response to MPTP. We produced reciprocal F1 hybrids by crossbreeding the MPTP-susceptible C57BL/6 strain with resistant BALB/c. These hybrids were compared to the parental strains using neural and behavioral measures in order to characterize the genetic transmission of MPTP-susceptibility. The F1 generation as a whole had a lower depletion of neostriatal dopamine levels than even found in BALB/c. Furthermore, there was no significant loss of tyrosine hydroxylase-positive cells in the substantia nigra and quick recovery from deficits in motor behavior in F1, herein resembling BALB/c. We suggest that several loci are involved in susceptibility to MPTP, and that the trait is under control of recessive susceptibility and/or dominant resistance alleles, which interact in F1, leading to extremely low susceptibility.

Genetic Dissection of Strain Dependent Paraquat-induced Neurodegeneration in the Substantia Nigra Pars Compacta

“…In this study we report that the C57BL/6J and SWR/J strains are differentially sensitive to systemic administration of paraquat—a finding that supports previous studies that detail differential genetic effects of this herbicide [20] and other neurotoxins, including MPTP [12], [19], [21], [22], [23]. We have exploited this pronounced strain difference to map chromosomal regions that modulate the differential vulnerability of dopaminergic cell to PQ.…”

Exercise protects against MPTP-induced neurotoxicity in mice

“…Several explanations can be proffered to account for this dichotomous type of protection including increased functional capacity of remaining DA neurons by compensatory mechanisms within spared neurons, insufficient time for restoration of the DA phenotype (in these cases expression of TH) in injured neurons (Fornai et al, 2000; Nishi et al, 1989; Tillerson et al, 2003), differences in strain (Hamre et al, 1999; Muthane et al, 1994; Sedelis et al, 2000), species (Terzioglu and Galter, 2008), and age of the experimental animals used in these studies (Tatton et al, 1992), differences in the experimental toxin used to generate the lesion (Smith and Zigmond, 2003), and/or differences in the exercise regimens (Cohen et al, 2003; Mabandla et al, 2004; Petzinger et al, 2007). …”

Chronic MPTP treatment produces hyperactivity in male mice which is not alleviated by concurrent trehalose treatment

“…Here, only males were studied as Parkinson's disease is more common in men [21]. C57BL/6 mice were used because this strain has been shown to be the most sensitive to MPTP treatment [22][23][24][25]. The behavioral assessments were selected based on previous descriptions of their sensitivity to MPTP treatment or other models of neurodegenerative disease (e.g., assessments of activity, cognition, grip strength, motor coordination, and olfaction) [26,27] and the focus was on short-and long-term alterations.…”